Innate Immunity

Innate immunity is the arm of host defence encoded in the germline rather than assembled by somatic recombination. It recognises conserved molecular patterns shared across whole classes of microbe, such as lipopolysaccharide, flagellin and unmethylated CpG DNA, through a limited set of pattern recognition receptors, chiefly the Toll-like and NOD-like receptors. Its components are epithelial barriers, antimicrobial peptides, complement, neutrophils, macrophages and natural killer cells. Because nothing has to be selected and expanded, it acts in minutes to hours where an adaptive response takes days.

The sensitivity is remarkable. Human TLR4, with MD-2 and CD14, detects lipid A at picogram concentrations, which is why parenteral products are held to endotoxin limits measured in units per millilitre. Defensins and cathelicidins reach micromolar concentrations in neutrophil granules, and complement can opsonise and lyse a bacterium with no prior exposure at all.

Innate immunity is not entirely memoryless: BCG vaccination produces trained immunity, an epigenetic reprogramming of monocytes that alters responses to unrelated pathogens for months. It remains non-specific, and that decides what an innate readout can tell you. A compound that raises cytokine output from cultured macrophages has demonstrated innate activation, not protection.

The recurring failure is contamination. Endotoxin at levels invisible to a purity chromatogram will activate TLR4 and produce exactly the macrophage activation a peptide is then credited with, so an innate assay run without an endotoxin measurement or a polymyxin B block is uninterpretable. The second error frames innate immunity as a dial to turn up, when sustained innate activation is what chronic inflammation consists of.